The interleukin 33 (IL-33) cytokine is the newest member of the interleukin 1 (IL-1) family. Because of its nuclear localization, it was originally described as “Nuclear Factor from High Endothelial Venules”. IL-33 is primarily expressed by fibroblasts and epithelial, endothelial and airway smooth muscle cells. IL-33 is the ligand for the IL-1 receptor-related protein ST2. The ST2 receptor is expressed in almost all innate immune cells (mast cells, basophils, eosinophils, neutrophils, natural killer (NK) cells and macrophages) and in NK T and T helper (Th) 2 cells. The interaction of IL-33 with ST2 on targeted cells can trigger the expression and secretion of pro-inflammatory, Th1, Th2 and Th17 cytokines and expression of chemokines involved in Th1, Th2 and innate immune effector functions (published papers and Hicks et al. manuscript in preparation). IL-33 binds to its specific surface receptor through its pro-inflammatory cytokine domain. In addition, IL-33 also has a N-terminal domain that contains a typical DNA-binding helix-turn-helix motif. In its nuclear uncleaved form, IL-33 interacts with histones 2A and 2B in heterochromatin promoting chromatin compaction and functioning as a potential transcriptional repressor. There is strong support showing that IL-33 is similar to other chromatin-associated cytokines (IL-1α and HMGB1) that appears to exert a dual-function, regulating transcriptional repression in the nucleus and signaling via a classic receptor acting as a potent pro-inflammatory cytokine Thus, it has been proposed that similarly to HMGB1, IL-33 may function as an ‘alarmin’ belonging to the larger family of damage-associated molecular pattern (DAMP) molecules.
The IL-33/ST2 axis plays pivotal roles in the patho-physiology of human inflammatory diseases as confirmed by their high levels of expression in diseased tissues. Elevated levels of either IL-33 and/or its soluble receptor ST2 are observed in rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriatic and ulcerative colitis, acute eosinophilic pneumonia, severe asthma, idiopathic pulmonary fibrosis, liver fibrotic diseases, atopic dermatitis, systemic sclerosis, autoimmune and trauma patients. Similar to its role in humans, the IL-33/ST2 axis has been shown to be critical in murine inflammatory models. IL-33 exacerbates collagen-induced arthritis (CIA), allergic conjunctivitis and experimental autoimmune encephalomyelitis (EAE), Interruption of IL-3/ST2 signaling with antibodies has been shown to be beneficial for the resolution of allergic airway inflammation and bleomycin-induced lung injury. It has also been shown recently that IL-33 is up-regulated in an IBD mouse model of chronic intestinal inflammation (Oboki et al, PNAS 2010 107 (43) 18581-18586).